Vortioxetine is a novel antidepressant developed by Tekeda Pharmaceuticals and H. Lundbeck A/S jointly, and used for the treatment of major depressive disorder. It is considered that the drug acts through a combination of two mechanisms: receptor activity modulation and reuptake inhibition. In vitro studies indicate vortioxetine is a 5-HT3 and 5-HT7 receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and a 5-HT transporter inhibitor. In vivo nonclinical studies indicate vortioxetine can elevate levels of neurotransmitters (serotonin, noradrenaline, dopamine, acetyl choline and histamine) in specific cerebral regions. It is anticipated that the multimodal activity profile of vortioxetine may bring clinical benefits to patients with major depressive disorder whose disease cannot be adequately controlled by currently available drugs. The drug was approved by FDA in September 2013 for marketing under the trade name Brintellix. Its tablets contain vortioxetine hydrobromide as the active pharmaceutical ingredient, and the strengths are 5 mg, 10 mg, 15 mg and 20 mg.
The chemical name of vortioxetine hydrobromide is 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide. Its English name is vortioxetine hydrobromide or LU AA21004. Its molecular formula is C18H22N2S.HBr. Its molecular weight is 379.36. Its chemical structural formula is shown below:

Patent document WO2003/029232A1 disclosed free base of vortioxetine and a preparation method thereof, also mentioned its solvates, isomers and pharmaceutically acceptable salts and uses in treating affective disorders. but did not provide preparation methods or characterization data of the above solvates, isomers or pharmaceutically acceptable salts of vortioxetine.
Patent documents WO2007/144005A1 and WO2008/113359A2 disclosed hydrobromide, hydrochloride, hydrochloride monohydrate, mesylate, fumarate, maleate, meso-tartrate, L-(+)-tartrate, D-(−)-tartrate, sulfate, phosphate and nitrate of vortioxetine in their crystalline forms as well as preparation methods and characterization data thereof. Specifically, examples 4a to 4i in WO2007/144005A1 disclosed multiple crystalline forms of vortioxetine hydrobromide including a Form, β Form, γ Form, a hydrate solvate and an ethyl acetate solvate. Additionally, the patent document pointed out that, among the above disclosed crystalline forms, the β Form of vortioxetine hydrobromide is the most stable form and has high melting point, low solubility and good non-hygroscopicity, thus it is particularly suitable for preparing tablets.
In studies, the inventors of the present invention found out that the multiple crystalline forms of vortioxetine hydrobromide disclosed in WO2007/144005A1 have the following disadvantages:
The α Form of vortioxetine hydrobromide is unstable. It transformed to the β Form of vortioxetine hydrobromide at room temperature.
The β Form of vortioxetine hydrobromide failed to maintain its original crystalline form in the stability competition slurry test.
The γ Form of vortioxetine hydrobromide is very unstable and is hygroscopic. Its hygroscopicity under low-humidity conditions was 2.0%.
The hydrate of vortioxetine hydrobromide is unstable and is hygroscopic. It lost water under high-temperature conditions.
The ethyl acetate solvate of vortioxetine hydrobromide is unstable. It lost ethyl acetate under high-temperature conditions and transformed to hydrate under high-humidity conditions.
Patent documents WO2009/062517A1 and WO2012/025123A1 disclosed uses of vortioxetine hydrobromide in treating affective disorders such as depressions and anxiety disorders and in treating cognitive defects and pain. WO2012/025123A1 reported a method of treating central nervous system (CNS) diseases in long-term treatment patients by using vortioxetine hydrobromide.
In order to meet the strict requirements for the solid forms of active substances in solid pharmaceutical preparations and expand the selection options of the solid forms of active substances in formulation development, it is necessary to develop novel salts of vortioxetine and crystals or crystalline forms thereof in this field.